Angiotensin II antagonists as a prophylactic or therapeutic drug for renal diseases

Abstract: This invention relates to prophylactic or therapeutic drug for diabetic nephropathy or glomerulonephritis, comprising, as an active ingredient, a compound or salt thereof represented by general formula (I) wherein R¹ stands for H or an optionally substituted hydrocarbon residue; R² stands for an optionally esterified carboxyl group; R³ stands for a group actually or potentially capable of forming an anion; X shows that the phenylene and phenyl groups bind to each other directly or through a spacer having an atomic chain length of two or less; n stands for 1 or 2; ring A stands for a benzene ring having an optional substituent in addition to R²; Y stands for a bond, -O-, -S(O) m - (wherein m stands for 0, 1 or 2), or -N(R⁴)- (wherein R⁴ stands for H or an optionally substituted alkyl group).

Description: FIELD OF THE INVENTION This invention relates to a prophylactic or therapeutic drug containing an angiotensin II antagonistic compound or salt thereof as the active constituent, for diabetic nephropathy or glomerulonephritis. BACKGROUND OF THE INVENTION The kidneys are a major target organ of hypertension. Prolonged hypertension induces various renal impairments, mainly through renovascular lesions. Among them, contraction of renal vessels and degenerative lesions of elastic fibers lead to further elevation of the blood pressure. It is generally believed that hypertension raises renal intraglomerular pressure, which overloads the glomeruli, stimulating fibrosis and enlargement of the mesangial region, which advances to hardening of the glomeruli. In diabetic nephropathy as well, elevation in intraglomerular pressure is followed by trace albuminuria, progressing to the sclerosis of the glomeruli. Eventually, renal functions decline, resulting in chronic renal failure requiring artificial dialysis therapy. In recent years, 20% of patients with end-stage renal failure who commence artificial dialysis have diabetic nephropathy as the underlying disease. The number of patients likely to receive artificial dialysis tends to increase year after year, posing a critical problem in the medical care system. At present, it is said that there are few ideal pharmaceutical therapies for chronic renal failure, and even that blood-pressure-lowering therapy may aggravate rather than improve renal failure. Angiotensin II antagonistic compounds are known as a therapeutic drug for cardiovascular diseases, e.g., hypertension, cardiac diseases (heart enlargement, heart failure, myocardial infarction, etc.), apoplexy, nephritis, etc. (European Patent Official Gazette (EPO) 459136A). The mechanism of their action is considered to be based on inhibition of binding to the angiotensin II receptor of angiotensin II, which possesses intense vasoconstrictive action. EP 459136A 1 describes the availability of angiotensin II antagonists in the treatment of nephropathy or nephritis. Many data of clinical and experimental studies have been reported on the relation between renal diseases and hypertension. It is now established that the kidneys are directly or indirectly involved in the onset of hypertension, and also are apt to be affected by hypertension. However, hypertension in chronic glomerulonephritis has been poorly elucidated, particularly as to causative factors, effects of hypertension on the course of nephritis, and prophylactic effects of blood pressure lowering therapy. Currently, nephritis is considered to be a clinical picture of different diseases with different entities. In accordance with the popularization of renal biopsy, renal diseases have been reviewed, resulting in their redefinition as a wide range of diseases characterized by proteinuria ("Shibata's Internal Medicine of the Kidneys," by Seiichi Shibata, Bunkodo, 1988). Glomerulonephritis, once regarded as a single disease, has been differentiated into glomerulonephritis, chronic pyelonephritis, IgA nephropathy, periarteritis nodosa, gout, diabetes, systemic lupus erythematosus (SLE), hepatic infarction, hereditary renal disease, amyloidosis, and Wegener's sarcoma. Diabetes associated with hypertension facilitates cardiovascular impairment and/or other organ complications, greatly affecting life expectancy. Accordingly, it is important to control blood pressure within the normal range during treatment, along with the control of diabetes and the improvement or prevention of arteriosclerosis. EP-A 400 835 discloses substituted benzimidazole compounds which may be of value in the treatment of diabetic nephropathy and glomerulonephritis. Compounds comprising in combination an alkoxy substituent in position 2 of the benzimidazole ring system and a carboxyl substituent in position 7 of the benzimidazole ring system are not disclosed. WO-A-9210182 discloses mainly imidazole compounds which may be useful for the treatment of diabetic nephropathy. The only benzimidazole compound disclosed in WO-A-9210182 does not comprise an alkoxy substituent in position 2 of a benzimidazole ring system in combination with a carboxyl substituent in position 7 of the benzimidazole ring system. The "FASEB JOURNAL", Volume 7 (3), February 1993, Page A 246, M. Böhm et al., discloses a dibenzimidazole compound as angiotensin II receptor antagonist. OBJECT OF THE INVENTION This invention provides a prophylactic or therapeutic drug for diabetic nephropathy or glomerular nephritis. SUMMARY OF THE INVENTION Under the above-mentioned circumstances, the inventors intensively studied to develop a drug for the prophylaxis or treatment of nephropathy or nephritis. Ultimately, they found that compounds possessing angiotensin II antagonistic action, represented by a particular structural formula, are very effective in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis. The present invention was thus accomplished. Namely, this invention relates to a prophylactic or therapeutic drug for diabetic nephropathy or glomerulonephritis, containing, as the active constituent, a compound or salt thereof represented by formula (I): wherein R 2 is a group of the formula: -CO-D'' wherein D'' is hydroxyl or C 1-4 alkoxy substituted with C 3-7 cycloalkoxycarbonyloxy; R 1 is C 1-6 alkyl; Y is -O- and R 3 is or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis or treatment of glomerulonephritis or diabetic nephropathy. DETAILED DESCRIPTION OF THE INVENTION The compounds used for prophylactic or therapeutic purposes, as represented by formula (I), are structurally very prominently characterized by the coexistence of R 2 , standing for an optionally esterified carboxyl group, and R 3 , standing for a group actually or potentially capable of forming an anion. This structural characteristic contributes to the onset of very intense prophylactic or therapeutic effect on diabetic nephropathy or glomerulonephritis. The compounds, possessing angiotensin II antagonistic action, represented by formula (I), can be used in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis. In formula (I), R 1 stands for C 1-6 alkyl. The alkyl group represented by R 1 is a straight chain or branched lower alkyl group having 1 to 6 carbon atoms, as exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl or hexyl. Y stands for -O-. Preferable examples of R3 include 2,5-dihydro-5-oxo-1,2,4-oxadiazole ring residue, 2,5-dihydro-5-thioxo-1,2,4-oxadiazole ring residue or 2,5-dihydro-5-oxo-1,2,4-thiadiazole ring residue having -NH or -OH group as proton donor and carbonyl group, thiocarbonyl group or sulfinyl group as proton acceptor simultaneously. In addition, the above-mentioned heterocyclic residue (R 3 ) have the following tautomeric isomers: In when Z=0, and g=0 the three tautomeric isomers a, b and c exist. The heterocyclic residue represented by the formula comprises all of these a, b and c. Moreover, R 3 may be a tetrazolyl group. As R 3 , a tetrazolyl group is preferable. R 2 is a group represented by the formula -CO-D'' [wherein D'' stands for hydroxyl group, or a lower (C 1-4 ) alkoxy whose alkyl moiety is substituted with lower (C 3-7 ) cycloalkoxycarbonyloxy (e.g. cyclohexyloxycarbonyloxy)]. For embodiment, the following substituents are listed for residue R 2 : -COOH and its salts and 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl. As the salt thereof, pharmaceutically allowable salts are listed, e.g., a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. Inorganic bases appropriate to form the said salt include alkali metals such as sodium and potassium, alkali soil metals such as calcium and magnesium, aluminum and ammonium. Organic bases appropriate to form the said salt include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine. Inorganic acids appropriate to form the said salt include hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. Organic acids appropriate to form the said salt include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Basic amino acids to form the said salt include arginine, lysine and ornithine. Acidic amino adds to form the said salt include aspartic acid and glutamic acid. As an active ingredient of the present invention, the compounds described in Examples of Japan Provisional Publication No. 364171/1992 and EP520423 are preferred. The compounds represented by general formula (I) were, for instance, disclosed in Provisional Publication Nos. 9373/1992 and 364171/1992, and EP520423, and can be manufactured as disclosed therein. Compound (I) or salts thereof possessing angiotensin II antagonistic action referred to in the present invention are of sufficiently low toxicity to be used as a pharmaceutical for animals, particularly mammals (e.g., humans, dogs, rabbits, rats, mice, etc.), in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis. Compound (I) or salts thereof represented by general formula (I) can be administered by the oral route, non-oral route, inhalation, rectal injection, or topical administration, as pharmaceutical constituents or preparations (e.g., powder, granules, tablets, pills, capsules, injection, syrup, emulsion, elixir, suspension, solution, etc.). At least one compound of the present invention can be used singly or in mixture with a carrier allowable as a pharmaceutical (adjuvant, vehicle, supportive agent, and/or diluting agent). The constituents of a pharmaceutical can be prepared according to the usual manner. In the present specification, the non-oral route includes subcutaneous injection, intravenous injection, intramuscular injection, peritoneal injection and intravenous drip. For prescription injection, sterile aqueous or oily suspension for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to the known method in said field. The sterile prescription agent for injection may be a non-toxic, non-orally administrable diluting agent such as aquous solution or a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer's solution, isotonic saline, etc. are allowed; as an ordinary solvent, or suspending solvent, sterile involatile oil can be used. For these purposes, any kind of involatile oil and fatty acid can be used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthetic mono- or di- or tri-glycerides. The suppository for rectal administration can be manufactured via a particular process, in which the drug is mixed with an appropriate, non-irritant supporting agent, e.g., cocoa butter or polyethylene glycol, that is solid at normal temperature but liquid at intestinal temperature and therefore melts in the rectum to release the drug. As the solid-type dosage form for oral administration, powder, granules, tablets, pills and capsules are listed as mentioned above. In these dosage forms, the active constituent compound can be mixed with at least one additive, including sucrose, lactose, cellulose, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, and glyceride. These dosage forms can also contain other type(s) of additive as usual, e.g., inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, α-tocopherol, antioxidant such as cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent, perfuming agent, etc. Tablets and pills can be further processed into enteric coated preparations. The liquid preparations for oral administration include emulsion, syrup, elixir, suspension and solution preparations allowable for medical use. These preparation may contain inactive diluting agents ordinarily used in said field, e.g., water. The dosage for a particular patient is determined according to age, body weight, general health conditions, sex, diet, administration time, administration method, excretion rate, drug combination, and severity of the illness being treated, in consideration of those or other factors. The compounds and salts thereof represented by general formula (I) can be safely used at low toxicity level; the daily dose varies with patient condition, body weight, type of compound, administration route, etc.; e.g., non-orally, i.e. for subcutaneous, intravenous, intramuscular or intrarectal use, approximately 0.01 - 50 mg/person/day, preferably 0.01 - 20 mg/person/day, and orally, approximately 0.01 - 150 mg/person/day, preferably 0.1 - 100 mg/person/day, are recommended. [Example] The invention is described in more detail with reference to examples. Example Preparation example The prophylactic or therapeutic drug containing compound (I) or a salt thereof, referred to in the present invention as the active constituent for diabetic nephropathy or glomerular nephritis, for instance, can be manufactured according to the following formula: 1. Capsules (1) 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg After (1) is mixed with (2), (3) and half of (4), the mixture is granulated. To the granules, the other half of (4) is added; the entire mixture is then sealed in a gelatin capsule. 2. Tablets (1) 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg After (1) is mixed with (2), (3), 2/3 of (4) and half of (5), the mixture is granulated. To the granules, the remaining amounts of (4) and (5) are added; the mixture is then press-shaped into a tablet. 3. Injection (reference) (1) 2-methylthio-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid disodium salt 10 mg (2) Inositol 100 mg (3) Benzylalcohol 20 mg One ampule 130 mg (1), (2) and (3) are dissolved in distilled water for injection to make the total volume 2 ml; the solution is sealed in an ampule. The entire process should be conducted under sterile conditions. 4. Capsules (1) (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg After (1) is mixed with (2), (3) and half of (4), the mixture is granulated. To the granules, the other half of (4) is added; the entire mixture is then sealed in a gelatin capsule. 5. Tablets (1) (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg After (1) is mixed with (2), (3), 2/3 of (4), and half of (5), the mixture is granulated. To the granules, the remaining amounts of (4) and (5) are added; the entire mixture is then press-shaped into a tablet. 6. Injection (1) 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid disodium salt 10 mg (2) Inositol 100 mg (3) Benzylalcohol 20 mg One ampule 130 mg (1), (2) and (3) are dissolved in distilled water for injection to make the total volume 2 ml; the solution is then sealed in an ampule. The entire process should be conducted under sterile conditions. 7. Capsules (reference) (1) 2-butyl-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg After (1) is mixed with (2), (3) and half of (4), the mixture is granulated. To the granules, the other half of (4) is added; the entire mixture is then sealed in a gelatin capsule. 8. Tablets (reference) (1) 2-butyl-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg After (1) is mixed with (2), (3), 2/3 of (4) and half of (5), the mixture is granulated. To the granules, the remaining amounts of (4) and (5) are added; the mixture is then press-shaped into a tablet. 9. Capsules (reference) (1) Pivaloyloxymethyl 2-butyl-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg After (1) is mixed with (2), (3) and half of (4), the mixture is granulated. To the granules, the other half of (4) is added; the entire mixture is then sealed in a gelatin capsule. 10. Tablets (reference) (1) Pivaloyloxymethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg Total 230 mg per tablet Components (1), (2), (3), a two-thirds portion of component (4) and a half portion of component (5) were mixed and granulated. To these granules, the remaining portions of components (4) and (5) were added, and the whole mixture tableted by compressive tableting. 11. Capsules (1) 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 10 mg (2) Lactose 90 mg (3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg One capsule 180 mg After (1) is mixed with (2), (3) and half of (4), the mixture is granulated. To the granules, the other half of (4) is added; the entire mixture is then sealed in a gelatin capsule. 12. Tablets (1) 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid 10 mg (2) Lactose 35 mg (3) Corn starch 150 mg (4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg One tablet 230 mg After (1) is mixed with (2), (3), 2/3 of (4) and half of (5), the mixture is granulated. To the granules, the remaining amounts of (4) and (5) are added; the mixture is then press-shaped into a tablet. The biologic activity of compounds and salts thereof possessing angiotensin-II-antagonistic action are described in Test Examples. Test Example 1 Antiproteinuric action in rats with subtotally (5/6) nephrectomy (focal glomerulosclerosis model; Meyer, T.W. and Renake, H.G.: Am. J. Physiol. 254, F856 (1988) or Yoshioka, T., Shiraga, H., Yoshida, Y., Fogo. A., Glick, A.D.: J. Clin. Invest. 82, 1614 (1988)) Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate Method: Five-week-old male rats were anesthetized by intraperitoneal injection of pentobarbital sodium and 2/3 of the right kidney was removed. One week later, the entire left kidney was removed under similar anesthesia. After two-week breeding, 24-hour urine was collected and the total protein content and albumin content in the urine were determined by the use of A/G-B test (Wako Pure Chemistry Co., Ltd.). On the basis of urinary protein and blood pressure (BP), the rats were divided into two groups (vehicle-treated rats and rats treated with 1 mg/kg/day, p.o. of compound 1). Rats undergoing nephrectomy of the left kidney alone were also used as sham operated rats. Compound 1 was suspended in gum-arabic and the suspension was orally administered once a day for eight weeks. At the 2nd, 4th, 6th and 8th week of the treatment, 24-hour urine was collected. Results: Table 1 summarizes the results. Urinary total protein and albumin began to markedly increase in vehicle-treated rats two weeks after surgery. Whereas, in rats treated with compound 1, these parameters did not increase and each parameter was rather significantly low six to eight weeks after the beginning of administration as compared with vehicle-treated rats. Since compound 1 suppresses aggravation of renal impairment, its efficacy in glomerulonephritis or diabetic nephropathy is expected. Antiproteinuric Action in subtotally (5/6) nephrectomized Rats Preadministration 2 weeks after the first dose 4 weeks after the first dose 6 weeks after the first dose 8 weeks after the first dose Urinary total protein (mg/100 g/24 hr) Vehicle (n=8-9) 33.1 ± 3.1 36.4 ± 5.2 39.4 ± 4.8 35.3 ± 6.1 55.1 ± 9.1 Compound 1 (n=9) 32.8 ± 5.4 30.9 ± 5.2 27.7 ± 4.0 17.6 ± 5.6 24.4 ± 2.7 Shams (n=6) 9.7 ± 0.7 14.9 ± 1.5 13.1 ± 1.4 8.3 ± 0.5 11.9 ± 1.3 Urinary albumin (mg/100 g/24 hr) Vehicle (n=8-9) 7.7 ± 2.6 12.0 ± 3.1 14.1 ± 3.0 15.1 ± 3.7 24.5 ± 7.1 Compound 1 (n=9) 7.3 ± 2.3 6.3 ± 2.9 6.8 ± 3.4 7.4 ± 4.0 5.6 ± 2.7 Shams (n=6) 2.1 ± 0.2 1.9 ± 0.2 2.1 ± 0.2 1.3 ± 0.2 1.6 ± 0.2 Values are expressed as mean ± standard error. Test Example 2 Antiproteinuric action in rats with non-insulin-dependent (NIDD) diabetes (Wistar fatty rats) (Ikeda, H., Shino, A., Matsuo, T., Iwatsuka, H., and Suzuoki, Z.: Diabetes, 30, 1045 (1981) or Kava, R.A., West, D.B., Lukasik, V.A., and Greenwood, M.R.C: Diabetes, 38, 159 (1989) Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate Method: On the basis of blood glucose level and urinary protein content, 11-week-old Wistar fatty rats were divided into two groups (vehicle-treated rats and rats treated with 1 mg/kg/day, p.o. of compound 1). Non-diabetic control rats (lean rats) were also used. Compound 1 was suspended in gum-arabic and the suspension was orally administered once a day for ten weeks. At the 2nd, 4th, 6th and 8th week of the treatment, 24-hour urine was collected. The urine was centrifuged at 3,000 rpm and a portion of the supernatant was desalted on a column (Pharmacia PD10). Urinary total protein content and albumin content were determined by Lowry and ELISA methods, respectively. Results: Table 2 summarizes the results. Urinary total protein content increased in vehicle-treated rats to about three times of the value in lean rats. This increase, however, was reduced to 1.2 - 1.5 times by the treatment with compound 1. Urinary albumin content also increased in vehicle-treated rats to about 100 times of the value in lean rats. This increase, however, was reduced to 20 - 30 times by the treatment with compound 1. Compound 1 did not affect blood glucose level. In non-insulin-dependent diabetic models, compound 1 is expected to be effective against diabetic nephropathy by decreasing the urinary protein without affecting the blood glucose level. Antiproteinuric Action in Rats with non-insulin-dependent diabetes 11 weeks 13 weeks 15 weeks 17 weeks 19 weeks 21 weeks Urinary total protein (mg/24hr) vehicle (n=6) 101±5 94±14 118±16 135±15 117±15 143±22 Compound 1 (n=6) 101±6 69±11 91±12 97±11 79±10 74±13 Lean (n=6) 55±2 36±3 51±3 51±3 45±2 45±2 Urinary albumin (mg/24 hr) vehicle (n=6) 2.9±0.4 24.6±7.5 42.7±9.0 46.4±10.4 38.6±6.4 28.6±5.2 Compound 1 (n=6) 6.5±4.1 11.2±3.9 14.8±6.1 21.8±8.2 10.7±3.9 15.4±3.7 Lean (n=6) 0.4±0.02 0.4±0.04 0.6±0.05 0.7±0.08 0.6±0.04 0.4±0.03 Values are expressed as mean ± standard error. Figures in parentheses denote the number of rats. Test Example 3 Acute Toxicity Test Compound 1: (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate The LD 50 of compound 1 is 2,000 mg/kg or more for 4-week-old Jcl:ICR mice (males and females) and for 5-week-old Jcl:Wister rats (males and females) via single oral administration.

Claims: Use of a compound of the formula (I): wherein R 2 is a group of the formula: -CO-D'' wherein D'' is hydroxyl or C 1-4 alkoxy substituted with C 3-7 cycloalkoxycarbonyloxy; R 1 is C 1-6 alkyl; Y is -O- and R 3 is or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis or treatment of glomerulonephritis or diabetic nephropathy. Use of claim 1, wherein R 1 is ethyl. Use of claim 1 or 2, wherein R 3 is a tetrazolyl group. Use of claim 3, wherein R 2 stands for C 1-4 alkoxylcarbonyl substituted with cyclohexyloxycarbonyloxy group. Use of claim 4, wherein said compound represented by the formula (I) is (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate. Use of claim 3, wherein said compound represented by the formula (I) is 2-ethoxy-1-[[2'-(1H-tetrazole-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid. Use of claim 2, wherein said compound represented by the formula (I) is 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid. Use of (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prophylaxis or treatment of sclerosis of the glomeruli.

Inventors: KUBO KEIJI, NISHIKAWA KOHEI, SHIBOUTA YUMIKO, KUBO, KEIJI, NISHIKAWA, KOHEI, SHIBOUTA, YUMIKO
Applicants: TAKEDA CHEMICAL INDUSTRIES LTD, TAKEDA CHEMICAL INDUSTRIES, LTD.
Application year: 1994
Main classification: A61K31
IPC codes: A61K31